ESG-1-60 and ESG-1-61: Novel dopamine D receptor-preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents

Study author Omar Soler-Cedeño, Ph.D.

Featured Paper of the Month – May 2025

Published in British Journal of Pharmacology by Omar Soler-Cedeño and Zheng-Xiong Xi of the NIDA IRP Addiction Biology Unit.

Summary

In this research paper, recently published in the British Journal of Pharmacology, we investigated three compounds – cariprazine, ESG-1-60, and ESG-1-61 – as potential treatments for cocaine use disorder. Cariprazine is an FDA-approved medication (a D3 receptor partial agonist with 3.6–13-fold selectivity for D3 over D2 receptors) used to treat schizophrenia, bipolar disorder, and major depressive disorder. ESG-1-60 and ESG-1-61 are cariprazine analogs designed to target both D3 and D2 receptors in the brain, with ~20-fold selectivity for D3 over D2 receptors. This relatively low selectivity is intentional, as we hypothesize that modest engagement of the D2 receptor – via partial activation or blockade – may enhance the anti-cocaine effects produced by D3 receptor partial activation or inhibition. In animal models, all three compounds significantly reduced both cocaine-taking and cocaine-seeking behaviors in both male and female rats. Notably, ESG-1-60 stood out by producing these beneficial effects without causing significant side effects such as sedation, locomotor inhibition, or rewarding or aversive responses. These findings suggest that ESG-1-60 holds strong potential as a novel therapeutic approach for cocaine addiction and merits further investigation.

Publication Information

Soler-Cedeño, Omar; Keegan, Bradley M; Alton, Hannah; Bi, Guo-Hua; Linz, Emily; Vogt, Caleb D; Gogarnoiu, Emma S; Shi, Lei; Newman, Amy Hauck; Xi, Zheng-Xiong

ESG-1-60 and ESG-1-61: Novel dopamine D receptor-preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents Journal Article

In: Br J Pharmacol, 2025, ISSN: 1476-5381.

Abstract | Links

@article{pmid40150927,

title = {ESG-1-60 and ESG-1-61: Novel dopamine D receptor-preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents},

author = {Omar Soler-Cedeño and Bradley M Keegan and Hannah Alton and Guo-Hua Bi and Emily Linz and Caleb D Vogt and Emma S Gogarnoiu and Lei Shi and Amy Hauck Newman and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/40150927/},

doi = {10.1111/bph.70021},

issn = {1476-5381},

year  = {2025},

date = {2025-03-01},

urldate = {2025-03-01},

journal = {Br J Pharmacol},

abstract = {BACKGROUND AND PURPOSE: Preclinical studies suggest that highly selective dopamine D receptor (DR) antagonists or partial agonists hold promise for treating substance use disorders. However, their limited effectiveness in reducing cocaine self-administration is a major drawback. This study investigated whether cariprazine (D receptor-preferring partial agonist) and its analogues ESG-1-60 and ESG-1-61 have enhanced efficacy in reducing cocaine-taking and cocaine-seeking behaviour.



EXPERIMENTAL APPROACH: In vitro BRET experiments were used to characterize the functional efficacies of cariprazine and its analogues. Intravenous cocaine self-administration and reinstatement models were used to evaluate efficacy in reducing cocaine-taking and cocaine-seeking behaviour. Optical intracranial self-stimulation (oICSS) procedures assessed effects on dopamine-dependent behaviour. Open-field locomotion, oral sucrose self-administration and conditioned place-preference were used to evaluate potential unwanted side effects.



KEY RESULTS: BRET functional assays indicated that cariprazine and ESG-1-60 are D receptor-preferring partial agonists, while ESG-1-61 is a D receptor-preferring antagonist/inverse agonist. All three compounds inhibited cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement schedules and reduced cocaine-induced reinstatement of drug-seeking behaviour in both male and female rats. The compounds did not alter locomotor behaviour but suppressed sucrose intake and dopamine-dependent oICSS. Cariprazine and ESG-1-61 produced significant place aversion, while ESG-1-60 did not. Chronic administration of ESG-1-60 inhibited cocaine self-administration.



CONCLUSIONS AND IMPLICATIONS: Novel D receptor-preferring compounds ESG-1-60 and ESG-1-61 were highly effective in reducing cocaine-taking and cocaine-seeking, under various reinforcement conditions. ESG-1-60 warrants further investigation as a new pharmacotherapy for treating cocaine use disorder as it is effective in these models and lacks unwanted behavioural effects.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

BACKGROUND AND PURPOSE: Preclinical studies suggest that highly selective dopamine D receptor (DR) antagonists or partial agonists hold promise for treating substance use disorders. However, their limited effectiveness in reducing cocaine self-administration is a major drawback. This study investigated whether cariprazine (D receptor-preferring partial agonist) and its analogues ESG-1-60 and ESG-1-61 have enhanced efficacy in reducing cocaine-taking and cocaine-seeking behaviour.

EXPERIMENTAL APPROACH: In vitro BRET experiments were used to characterize the functional efficacies of cariprazine and its analogues. Intravenous cocaine self-administration and reinstatement models were used to evaluate efficacy in reducing cocaine-taking and cocaine-seeking behaviour. Optical intracranial self-stimulation (oICSS) procedures assessed effects on dopamine-dependent behaviour. Open-field locomotion, oral sucrose self-administration and conditioned place-preference were used to evaluate potential unwanted side effects.

KEY RESULTS: BRET functional assays indicated that cariprazine and ESG-1-60 are D receptor-preferring partial agonists, while ESG-1-61 is a D receptor-preferring antagonist/inverse agonist. All three compounds inhibited cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement schedules and reduced cocaine-induced reinstatement of drug-seeking behaviour in both male and female rats. The compounds did not alter locomotor behaviour but suppressed sucrose intake and dopamine-dependent oICSS. Cariprazine and ESG-1-61 produced significant place aversion, while ESG-1-60 did not. Chronic administration of ESG-1-60 inhibited cocaine self-administration.

CONCLUSIONS AND IMPLICATIONS: Novel D receptor-preferring compounds ESG-1-60 and ESG-1-61 were highly effective in reducing cocaine-taking and cocaine-seeking, under various reinforcement conditions. ESG-1-60 warrants further investigation as a new pharmacotherapy for treating cocaine use disorder as it is effective in these models and lacks unwanted behavioural effects.